DELAYED TREATMENT WITH AN ADENOSINE KINASE INHIBITOR, GP683, ATTENUATES INFARCT SIZE IN RATS WITH TEMPORARY MIDDLE CEREBRAL-ARTERY OCCLUSION

Background and Purpose-Brain ischemia is associated with a marked incr ease in extracellular adenosine levels. This results in activation of cell surface adenosine receptors and some degree of neuroprotection, A denosine kinase is a key enzyme controlling adenosine metabolism. Inhi bition of this enzyme enhances the levels of endogenous brain adenosin e already elevated as a result of the ischemic episode. We studied a n ovel adenosine kinase inhibitor (AKI), GP683, in a rat focal ischemia model. Methods-Four groups of 10 adult Sprague-Dawley rats were expose d to 90 minutes of temporary middle cerebral artery (MCA) occlusion. A nimals were injected intraperitoneally with vehicle, 0.5 mg/kg, 1.0 mg /kg, or 2.0 mg/kg of GP683 30, 150, and 270 minutes after the inductio n of ischemia by a researcher blinded to treatment group. The animals were euthanatized 24 hours after MCA occlusion, and brains were staine d with 2,3,5-triphenyltetrazolium chloride. We measured brain temperat ures in a separate group of 6 rats before and after administration of 1.0 mg/kg GP683. Results-All treated groups showed a reduction in infa rct volumes, but a significant effect was observed only in the 1.0 mg/ kg-dose group (44% reduction, P=0.0077). Body weight, physiological pa rameters, neurological scores, and mortality did not differ among the 4 groups. No apparent behavioral side effects were observed. Brain tem peratures did not change after drug injection. Conclusions-Our results indicate that the use of AKIs offers therapeutic potential and may re present a novel approach to the treatment of acute brain ischemia. The therapeutic effect observed was not caused by a decrease in brain tem perature.